Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yet, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. In Phase I, we showed that M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation by engaging non-inflammasome dependent innate pathways. In this Phase II proposal, we will explore how M2SR stimulates antiviral immune responses in older subjects in the following aims: Aim 1. Examine dendritic cell survival and function in response to M2SR infection. Aim 2: Determine the molecular mechanism of interferon stimulated gene expression regulation in dendritic cells. Aim 3: Evaluate the early immune response in human subjects vaccinated with M2SR. These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the fundamental innate immune defects that contribute to failure to mount protective immunity. The outcome of the experiments is expected to have high impact, both with respect to the fundamental understanding of the underlying mechanism of flu-related illnesses in the susceptible elderly population, and in providing a basis with which to design vaccine and immunotherapeutic interventions.